Compounds of the formula ##STR1## in which R1, R1 ', R2, R2 ' and R3 independently represent a C1-6 alkyl radical, in addition to which R3 may represent a hydrogen atom, the alkyl radicals together containing in all at least 8 carbon atoms, are provided for use as highly sterically hindered bases in chemical syntheses.
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5. In a process of chemical synthesis using a highly sterically hindered base the improvement comprising the use of a guanidine of formula: ##STR16## in which R1, R'1, R2, R'2 and R3 independently represent a C1 -C6 alkyl radical, in addition to which R3 may represent a hydrogen atom, the alkyl radicals together containing in all at least 8 carbon atoms, as a highly sterically hindered base.
1. A highly sterically hindered guanidine of formula I ##STR11## in which: R1, R1 ', R2, R2 ' and R3 independently represent a hydrogen atom, a methyl, ethyl, isopropyl or tertiary butyl radical, R1, R'1, R2, R'2 and R3 together containing in all at least 8 carbon atoms, with the proviso that when the four radicals R1, R1 ', R2, R2 ', all represent a methyl radical or all represent an ethyl radical, then R3 is not a tertiary butyl radical.
2. A high sterically hindered guanidine according to
N-t-butyl-N',N'-diethyl-N",N"-diisopropylguanidine, N-ethyl-N',N',N",N"-tetraisopropylguanidine, N,N,N',N'-tetraisopropylguanidine, or N-t-butyl-N',N',N",N"-tetraisopropylguanidine.
3. A process according to
4. A process for the preparation of a guanidine according to
(a) the process, in which R1, R'1, R2 and R'2 are all C3-6 alkyl radicals, by the action of phosgene on a thiourea of formula IV: ##STR13## in a solvent to obtain a Vilsmeier salt of formula III: ##STR14## and reacting an amine of formula II:
R3 NH2 (II) with said Vilsmeier salt, and (b) the process in which R1, R'1, R2 and R'2 are all methyl or ethyl, by the action of phosgene on a urea of formula V: ##STR15## in a solvent to obtain a Vilsmeier salt of formula III, and reacting the amine of formula II: R3 NH2 (II) with said Vilsmeier salt. |
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This invention relates to new highly sterically hindered guanidines, to processes for their production and to their use in chemical syntheses.
Generally, highly sterically hindered organic bases play an important part in chemical syntheses.
Among the highly hindered strong bases, those of the amidine type are relatively few in number, but are particularly interesting in the field of syntheses. However, these amidine bases are attended by the disadvantage of being relatively expensive.
It is for this reason that the present invention seeks to provide a new series of highly hindered organic bases which may be produced from relatively inexpensive products.
More particularly, the present invention relates to a series of guanidines which are stronger and more hindered than the amidine bases hitherto used. The compounds in question correspond to the following formula: ##STR2## in which R1, R'1, R2, R'2 and R3 independently represent a C1 -C6 alkyl radical, in addition to which R3 may represent a hydrogen atom, the alkyl radicals together containing in all at least 8 carbon atoms.
The present invention also provide highly sterically hindered guanidines of formula (I) in which R1, R1 ', R2, R2 ' and R3 independently represent a hydrogen atom, a methy, ethyl, isopropyl or tertiary butyl radical, R1, R1 ', R2, R2 ' and R3 together containing in all at least 8 carbon atoms, with the proviso that when the four radicals R1, R1 ', R2, R2 ', all represent a methyl radical or all represent an ethyl radical, then R3 is not a tertiary butyl radical.
Among the substituent alkyl radicals, the methyl, ethyl, isopropyl or t-butyl radicals are mentioned in particular.
The new guanidines according to the present invention may be prepared in particular by reacting an amine corresponding to the following formula
R3 NH2 (II)
with a Vilsmeier salt corresponding to the following formula ##STR3##
The Vilsmeier salt may be prepared by treating the corresponding tetra-alkyl urea in a solvent, particularly benzene or ether, with phosgene in toluene or in ether at 0°C ##STR4##
This process, which is illustrated in scheme 1, may be used in particular for producing guanidines corresponding to the following formulae: ##STR5##
In cases where the guanidines to be prepared are more hindered, such as those corresponding to the following formulae: ##STR6## it is not possible to prepare the Vilsmeier salts from tetraisopropyl urea. Instead, they have to be prepared as shown in scheme 2 from tetraisopropyl thiourea under the same conditions as before.
With regard to the most highly hindered urea (6), it is is necessary, in order to obtain a satisfactory yield of the amine over the Vilsmeier salt, to introduce the Vilsmeier salt in the form of the corresponding anion by reacting the t-butyl amine in the presence of t-butyl lithium.
The guanidines according to the present invention may be widely used in the field of chemical syntheses.
Thus, the guanidines according to the invention may be used in the production of esters by alkylating carboxylic acid amidinium salts with alkyl halides, as already described in the literature: N. Ono, T. Yanada, T. Saito, K. Tanaka and A. Kaji, Bull. Chem. Soc. Jap., (1978), 51, 2401, this process being of particular interest for the production of highly hindered carboxylic acid esters.
The carboxylic acid salts with the guanidines according to the invention lead to an extremely fast and clean reaction when they react with alkyl iodides to give the corresponding esters in very high yields.
Examples of reactions using the compounds according to the present invention are illustrated below in schemes 3 and 4: ##STR7##
In scheme 3, the hederagenin reacts rapidly in DMF at room temperature with methyl iodide in the presence of the compound according to the invention to give the corresponding methyl ester in a yield of 88%.
In scheme 4, the adamantanoic acid reacts almost immediately in benzene in the presence of isopropyl iodide at ambient temperature to give the isopropyl derivative in a yield of 91%.
The compounds according to the invention may also be used in the preparation of Δ-2 and Δ-3-cholestene from 3-β-hydroxy cholestane tosylate.
According to the literature, this reaction takes place under reflux at 170°C in collidine, giving a yield of 60% in 6 hours in accordance with the following scheme: ##STR8##
When the tosylate is heated for 24 hours at 120°C with the guanidine (1) according to the present invention, a mixture of Δ-2 and Δ-3-cholestene is obtained in a yield of 80% after purification by column chromatography.
When the tosylate is heated for 24 hours at 120°C with the compound of formula (3), the mixture of Δ-2 and Δ-3-cholestene is obtained in a yield of 79% after column chromatography.
It is also possible to alkylate 2,6-dimethyl phenol in a yield of 80% exclusively on the oxygen with the compound of formula (1) by way of the corresponding phenoxide, followed by the addition of methyl iodide at ambient temperature.
Alkylation of ethyl acetoacetate is also possible using the compound of formula (1) as base.
The addition of an equivalent of the compound of formula (1) to a solution of ethyl acetoacetate in ether, followed by the addition of an excess of methyl iodide, gives 83% of the mono-C-alkylated compound (a) accompanied by only traces of the dimethylated compound (b) after a reaction time of approximately 5 minutes: ##STR9##
The mono-C-alkylated compound may be reconverted into the di-C-alkylated derivative (b) in a yield of 83% in the presence of another quantity of the compound of formula (1) and an excess of methyl iodide.
The following Examples are intended to illustrate other features and advantages of the invention without limiting it in any way.
PAC Preparation of N-t-butyl-N',N',N",N"-tetramethyl guanidineA solution of 5 g (0.043 mole) of N,N,N',N'-tetramethylurea in 10 ml of dry benzene is added dropwise over a period of 10 minutes with stirring at 0°C to a solution of 8.29 g (0.084 mole) of phosgene in 25 ml. of toluene.
The mixture is heated to room temperature and then stirred for 2 hours. The solvents and the excess phosgene are evaporated, leaving the following compound ##STR10## in the form of a hygroscopic white crystalline solid.
15 ml of dry t-butylamine (0.143 mole) is added with stirring to a solution of this solid in 10 ml of dry acetonitrile at a temperature of 0° C.
The mixture is heated to room temperature and then refluxed for 2 hours. The solvents are evaporated and the residue is triturated four times with 50 ml of ether.
20 ml of a 50% aqueous sodium hydroxide solution is added to the residue. After cooling of the mixture, it is extracted with 250 ml of ether. The extract is dried over anhydrous sodium sulfate, filtered and evaporated to give a pale yellow oil.
Distillation gives 6.25 g of the title compound in the form of a colourless liquid (yield 85%). This product has the following characteristics:
Bp. 760 mm 178°-183°C
νmax (liquid film) 1620 cm-1 (C═N).
δ (CDCl3): 1.22 (9H, S, N.C(CH3)3) and 2.67 (12H, S, (CH3)2 N.C.N(CH3)2).
m/e: 171 (M+).
PAC Preparation of N,N,N',N'-tetraethyl urea100 ml of anhydrous diethyl amine (0.965 mole) are added dropwise with stirring at -78°C to a solution of 8.72 g of phosgene (0.089 mole) in 30 ml of dry ether.
25 ml of ether are then added and the mixture is heated to room temperature and stirred for 18 hours.
The product is filtered and the residue is washed with ether. The filtrate is then evaporated, leaving an orange oil.
The product is dissolved in chloroform and the solution is washed with a 1M aqueous hydrochloric acid solution, water, a saturated sodium bicarbonate solution, water and finally with brine.
Drying over anhydrous sodium sulfate, filtration and evaporation give 14.7 g of N,N,N',N'-tetraethyl urea in the form of a chromatographically homogeneous pale yellow oil (yield 97%) having the following characteristics:
Bp.: 213°-215°C (lit. 205°C).
νmax 2975, 2940, 2875 (C--H) and 1645 cm-1 (C═O, urea).
δ (CDCl3): 1.09 (12H, t, J=7 Hz, 4×.CH2.CH3) and 3.17 (8H, q, J=7 Hz, 4×.CH2.CH3).
m/e: 172 (M+).
PAC Preparation of N-t-butyl-N',N',N",N"-tetraethyl guanidine39.5 g of phosgene (0.40 mole) in 100 ml of dry ether are added to 12.0 g of N,N,N',N'-tetraethyl urea (0.07 mole) and the mixture is left standing at room temperature for 24 h.
The ether and the excess phosgene are evaporated to give an orange gum which is dissolved in 10 ml of anhydrous acetonitrile.
30 ml of dry t-butyl amine (0.28 mole) are carefully added to the resulting solution cooled in an ice bath and the mixture left standing for 15 hours at room temperature.
The solvents are evaporated and the residue is triturated with ether to give a white crystalline solid. The solid is mixed with 50 ml of a 50% aqueous potassium hydroxide solution and extracted with ether. The ethereal extract is dried over anhydrous sodium sulfate, filtered and evaporated to give a pale yellow oil.
Distillation in vacuo gives 7.64 g of a colourless liquid (yield 48%). This product, which corresponds to the title compound has the following characteristics:
Bp: 60°-62°C (0.05 mm Hg).
νmax (liquid film): 2975, 2940, 2875 (C--H) and 1620 cm-1 (C═N).
δ (CDCl3): 1.00 (12H, t, J=7 Hz, 4×.CH2.CH3), 1.21 (9H, S, .C(CH3)3) and 3.00 (8H, q, J=7 Hz, 4×.CH2.CH3).
m/e: 227 (M+).
Found: C, 68.72; H, 12.82; N, 18.70; C13 H29 N3. Calculated: C, 68.66; H, 12.85; N, 18.48%.
PAC Preparation of N,N-diethyl-N',N'-diisopropylurea50 ml of diethylamine (0.48 mole) are added to 5.699 g of N,N-diisopropyl carbamoyl chloride (0.035 mole) in a flask equipped with a reflux condenser. The reaction is exothermic and the mixture is left standing for 3 hours at room temperature.
The excess diethylamine is evaporated and the product is distributed between ethyl acetate and water. The organic phase is washed with aqueous 1M hydrochloric acid, water, a saturated sodium bicarbonate solution, water and finally with brine.
The solution is dried over anhydrous sodium sulfate, filtered and evaporated to give a chromatographically homogeneous (thin-layer chromatography, ether/hexane 1:1) colourless liquid.
Distillation under reduced pressure gives 4.911 g of a colourless liquid corresponding to the title compound(yield 70%) which has the following properties:
Bp.: 54°-57°C (0.03 mmHg).
νmax (liquid film): 1645 cm-1 (C═O, urea).
δ (CDCl3): 1.05 (6H, t, J=7 Hz, 2×CH2.CH3) 1.23 (12H, d, J=7 Hz, 2×CH3.CH.CH3) 3.02 (4H, t, J=7 Hz, 2×.CH2.CH3) and 3.30 (2H, septet, J=7 Hz, 2×CH3.CH.CH3).
m/e: 200 (M+), 185 (M+ --CH3), 157 (M+ --C3 H7) and 100 (M+ --C4 H10 NO).
Found: C, 65.93; H, 12.18; N, 14.10; C11 H24 N2 O. Calculated: C, 65.95; H, 12.08; N, 13.99%.
PAC Preparation of N-t-butyl-N',N'-diethyl-N",N"-diisopropyl guanidineA solution of 20 ml of phosgene (0.28 mole) in 50 ml of dry ether is added to a solution of 11.305 g (0.05 mole) of N,N-diethyl-N',N',-diisopropyl urea in 40 ml of dry ether.
The mixtue is left standing at room temperature for 9 days during which a white crystalline precipitate is formed. The ether and the excess phosgene are evaporated to give a white crystalline hygroscopic solid having the following characteristics:
δ (CDCl3): 1.10 (6H, t, J=7 Hz, 2×.CH2.CH3) 1.27 (12H, d, J=7 Hz, 2×H3 C.CH.CH3) 3.12 (4H, q, J=7 Hz, 2×.CH2.CH3) and 3.70 (2H, septet, J=7 Hz, 2×H3 C.CH.CH3).
The product is dissolved in 20 ml of dry distilled acetonitrile and 40 ml of t-butylamine added to the resulting solution.
The mixture is heated to reflux temperature over a period of 72 hours and the solvents are evaporated. The product is thoroughly triturated with ether and then treated with a 50% aqueous potassium hydroxide solution. The mixture is extracted with ether and the ethereal extracts are washed with brine.
After drying over anhydrous sodium sulfate, filtration and evaporation, a pale yellow liquid is obtained. The product is dried over potassium hydroxide pellets and distilled in vacuo to give 8.32 g of the title compound in the form of a colourless liquid (yield 60%).
The traces of N,N-diethyl-N',N',-diisopropyl urea present are eliminated by treatment with an excess of hydrogen chloride in ether, followed by trituration of the insoluble residue with ether. The title compound is liberated using a 50% aqueous potassium hydroxide solution, followed by extraction with ether and evaporation of the ethereal extract to give a colourless liquid which has the following properties:
Bp.: 74°-77°C (0.09 mmHg).
νmax (liquid film): 1614 cm-1 (C═N).
δ (CDCl3): 1.03 (6H, t, J=7 Hz, 2×.CH2.CH3) 1.20 (12H, d, J=7 Hz, 2×H3 C.CH.CH3) 1.23 (9H, S, .C(CH3)3) 2.97 (4H,q, J=7 Hz, 2×.CH2.CH3) and 3.35 (2H, septet, J=7 Hz, 2×CH3.CH.CH3).
m/e: 255 (M+).
Found: C, 70.69; H, 13.02; N, 16.46; C15 H33 N3. Calculated: C, 70.53; H, 13.02; N, 16.45%.
PAC Preparation of N-ethyl-N',N',N",N"-tetraisopropyl guanidineA solution of 2 ml phosgene (27.92 moles) in 10 ml of dry ether is added to 0.963 g of distilled, dry N,N,N',N'-tetraisopropyl guanidine (3.95 moles). A precipitate is rapidly formed and the mixture left standing at room temperature for 2 hours. The solvent and the excess phosgene are evaporated to give a white solid. The product is dissolved in 3 ml of distilled dry acetonitrile and 5 ml of dry ethylamine are added dropwise to the resulting solution at 0°C
The mixture is heated to room temperature and the solvents are evaporated. The residue is triturated with ether and then treated with an excess of a 50% potassium hydroxide solution.
The product is extracted with ether and treated with brine.
After drying over anhydrous sodium sulfate, filtration and evaporation, 0.855 g of a pale yellow oil are obtained (yield 85%).
Drop-by-drop distillation in vacuo gives a colourless oil which has the following characteristics:
νmax (film): 1610 cm-1 (C═N).
δ (CDCl3): 1.10 (3H, t, J=7 Hz, CH2.CH3) 1.15 (12H, d, J=7 Hz, 2×H3 C.CH.CH3) 1.25 (12H, d, J=7 Hz, 2×H3 C.CH.CH3) 3.18 (2H, q, J=7 Hz, CH2.CH3) 3.40 (2H, septet, J=7 Hz, 2×H3 C.CH.CH3) and 3.76 (2H, septet, J=7 Hz, 2×H3 C.CH.CH3).
m/e: 255 (M+) and 212 (M+ --C3 H7).
PAC Preparation of N,N,N',N'-tetraisopropyl guanidineA solution of 2 ml of phosgene (27.92 mmoles) in 10 ml of dry ether is added to 1.078 g of distilled, dry N,N,N',N'-tetraisopropyl thiourea (4.42 mmoles). A precipitate is rapidly formed and the mixture is left standing at room temperature for 2 h.
The solvent and the excess phosgene are evaporated, leaving a white solid. The product is dissolved in 2 ml of distilled dry acetonitrile and an excess of ammonia gas is injected into the solution at 0°C
The solvent is evaporated, leaving a pale brown crystalline solid which is treated with a 50% aqueous potassium hydroxide solution and extracted with ether. The ethereal extracts are dried over anhydrous sodium sulfate, filtered and evaporated to give 0.874 g of a pale orange oil (yield 81%).
Drop-by-drop distillation in vacuo gives a colourless oil which corresponds to the title compound and which has the following properties:
νmax (film): 3350-3100 (NH), 2970, 2930, 2870 (CH) and 1590 cm-1 (C═N).
δ (CDCl3): 1.20 (24H, d, J=7 Hz, 4×H3 C.CH.CH3) 3.65 (4H, septet, J=7 Hz, 4×H3 C.CH.CH3) and 5.55 (1H, br. N.H.) (the addition of D2 O causes the signal at δ 5.55 to disappear)
m/e: 227 (M+) and 184 (M+ --C3 H7).
PAC Preparation of the methyl ester of hederagenin0.41 g of hederagenin (0.87 mmole) is added to a solution of 0.199 g of N-t-butyl-N',N',N",N"-tetramethylguanidine (1.16 mmoles) in 3 ml of dry dimethyl formamide. The mixture is heated until the solid dissolves and is then left to cool to room temperature.
1 ml of iodomethane (0.016 mole) is then added and the mixture is left standing at room temperature for 45 mins.
50 ml of water are then added to the reaction mixture and a white crystalline precipitate of hederagenin methyl ester is formed. The product is filtered and washed with water before being dried in vacuo to give 0.371 g of the title compound (yield 88%).
The product thus obtained has a melting point of 231°-233°C (lit. 240°C).
PAC Preparation of the isopropyl ester of 1-adamantane carboxylic acid0.289 g of 1-adamantane carboxylic acid are dissolved in 3 ml of distilled, dry benzene and 0.344 g of N-t-butyl-N',N',N",N"-tetramethyl guanidine (2.01 mmoles). 1 ml of 2-iodopropane (10.02 mmoles) is added to the resulting solution and the mixture is left standing at room temperature. After about 5 minutes, a heavy yellow oil separates from the solution.
After 30 minutes, the solvent and the excess isopropyl iodide are evaporated to give a yellow oil. The product is distributed between ether and aqueous 1M hydrochloric acid and the aqueous phase is re-extracted with ether. The combined ethereal extracts are washed with water, a saturated aqueous sodium bicarbonate solution, water, a 5% aqueous sodium thiosulfate solution and finally with brine.
After drying over anhydrous sodium sulfate, filtration and evaporation, 0.32 g of a chromatographically homogeneous colourless oil which crystallises on standing is obtained (yield 91%).
This ester has a melting point of 29°-30°C
PAC Reaction of 3-β-cholestanyl tosylate with N-t-butyl-N',N'-diethyl-N",N"-diisopropyl guanidine0.269 g of 3-β-cholestanyl tosylate (0.50 mmole) is mixed with 1.34 g of N-t-butyl-N',N'-diethyl-N",N"-diisopropyl guanidine (5.25 mmoles) and heated for 20 hours to 120°C The product is then distributed between an excess of aqueous 1M hydrochloric acid and ether. The aqueous phase is re-extracted with ether and the combined extracts are washed with water, a saturated aqueous sodium bicarbonate solution, water and finally with brine.
After drying over anhydrous sodium sulfate, filtration and evaporation, a colourless oil is obtained. The product is purified by column chromatography on silica gel (eluent: ether/hexane 1:4) to give a mixture of Δ-2-cholestene and Δ-3-cholestene in the form of a white crystalline solid (0.145 g, yield 79%).
Crystallisation in a mixture of ethyl acetate and methanol gives long needles having the following characteristics:
Mp.: 68°-71°C (lit. 67°-68°C).
[α]D20 =+58 (C1.1% of CHCl3) (lit. +62, 4.9% in CHCl3).
PAC Reaction of ethyl acetoacetate with N-t-butyl-N',N',N",N"-tetramethyl guanidine/iodomethane(A) A solution of 1.35 g of N-t-butyl-N',N',N",N"-tetramethyl guanidine (7.89 mmoles) in 3 ml of distilled, dry ether is added to a solution of 1.023 g of distilled ethyl acetoacetate (7.87 mmoles) in 3 ml of distilled dry ether. 1 ml of iodomethane (16.1 mmoles) is added dropwise to the cooled mixture and the product is heated to room temperature and then left standing for 1 hour.
The mixture is filtered and the residue is washed with ether. The filtrate is evaporated to give 0.94 g of mono-C-methylated ethyl acetoacetate (yield 83%) containing less than 5% of dimethylated derivatives (NMR-spectroscopy).
(B) The 0.94 g of the above product are dissolved in 3 ml of distilled anhydrous ether and a solution of 1.50 g of N-t-butyl-N',N',N",N"-tetramethylguanidine (8.77 mmoles) in 3 ml of distilled dry ether is added to the resulting solution. 2 ml of iodomethane (32.2 moles) are then added and the mixture left standing for 2 hours.
The product is distributed between ether and water. The ethereal extracts are washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give 0.98 g of a colourless oil (yield 87%) of di-C-methylated compound and 13% of the starting compound (NMR-spectroscopy).
PAC Reaction of 2,6-dimethyl phenol with N-t-butyl-N',N',N",N"-tetramethyl guanidine/iodomethane0.547 g of N-t-butyl-N',N',N",N"-tetramethyl guanidine (3.20 mmoles) and then 1 ml of iodomethane (16.1 mmoles) are added to a solution of 0.349 g of 2,6-dimethylphenol (2.86 mmoles) in 2 ml of anhydrous ether.
After 30 minutes, the solvents are evaporated and the product is distributed between ether and an aqueous 1M hydrochloric acid solution. The ethereal extract is dried over anhydrous sodium sulfate, filtered and evaporated to give 0.31 g of 2,6-dimethyl anisole in the form of a pale yellow chromatographically homogeneous oil (NMR, IR, TLC); yield 80%.
Elliott, John D., Barton, Derek H. R., Gero, Stephan D.
| Patent | Priority | Assignee | Title |
| 4992200, | Jan 16 1986 | Cognis Corporation | Recovery of precious metals |
| 5262568, | Mar 02 1990 | STATE OF OREGON ACTING BY ND THROUGH THE OREGON STATE BOARD OF HIGHER EDUCATION, ACTING FOR AND ON BEHALF OF OREGON HEALTH SCIENCES UNIVERSITY; STATE OF OREGON, ACTING BY AND THROUGH THE OREGON STATE BOARD OF HIGHER EDUCATION, ACTING FOR AND ON BEHALF OF THE OREGON HEALTH SCIENCES UNIVERSITY AND THE UNIVERSITY OF OREGON | Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists |
| 5312840, | Jul 10 1986 | State of Oregon, Acting by and Through the Oregon State Board of Higher | Substituted guanidines having high binding to the sigma receptor and the use thereof |
| 5336689, | Mar 02 1991 | State of Oregon, Acting by and Through the Oregon State Board of Higher | Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists |
| 5385946, | Jul 10 1986 | State of Oregon, Acting by and Through the Oregon State Board of Higher | Method for treating hypertension with disubstituted granidine compounds |
| 5403861, | Feb 08 1991 | Wyeth | Substituted guanidines and derivatives thereof as modulators of neurotransmitter release and novel methodology for identifying neurotransmitter release blockers |
| 5478863, | Jul 10 1986 | State of Oregon, Oregon Health Sciences University of Oregon | Substituted guanidines having high binding to the sigma receptor and the use thereof |
| 5502255, | Jul 10 1986 | State of Oregon acting by and through the Oregon State Board of Higher | Substituted guanidines having high binding to the sigma receptor and the use thereof |
| 5559154, | Mar 02 1990 | Oregon State Board of Higher Education; Oregon Health Sciences University; University of Oregon | Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists |
| 5574070, | May 25 1990 | State of Oregon, Acting by and Through the Oregon State Board of Higher; The University of Oregon | Substituted guanidines having high binding to the sigma receptor and the use thereof |
| 5604228, | Jul 10 1986 | State of Oregon, Acting by and Through the Oregon State Board of Higher; University of Oregon | Substituted guanidines having high binding to the sigma receptor and the use thereof |
| 5612332, | Mar 19 1984 | ALTEON INC | Di- and triaminoguanidines, and methods of use |
| 5614630, | Feb 08 1991 | Wyeth | Acenaphthyl substituted guanidines and methods of use thereof |
| 5622968, | Feb 08 1991 | Wyeth | Acenaphthyl substituted guanidines and methods of use thereof |
| 5637622, | Mar 02 1990 | State of Oregon, Acting by and Through the Oregon State Board of Higher | Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists |
| 5637623, | Feb 08 1991 | Wyeth | Substituted adamantyl guanidines and methods of use there of |
| 5652269, | Feb 08 1991 | Wyeth | Substituted hydrazinecarboximidamides and methods of use thereof |
| 5670519, | Feb 08 1991 | Wyeth | Acenaphthyl-substituted guanidines and methods of use thereof |
| 5672608, | Feb 08 1991 | Wyeth | Acenaphthyl substituted guanidines and methods of use thereof |
| 5677348, | Feb 08 1991 | Wyeth | Substituted aminoguanidines and methods of use thereof |
| 5681861, | Feb 08 1991 | Wyeth | Aminoguanidines and methods of use of same |
| 5686495, | Feb 08 1991 | Wyeth | Substituted hydrazinedicarboximidamides and methods of use thereof |
| 5696290, | Sep 12 1994 | ABLECO FINANCE LLC, AS COLLATERAL AGENT | Synthesis of penta-substituted guanidines |
| 5741661, | Feb 08 1991 | Wyeth | Substituted guanidines and derivatives thereof as modulators of neurotransmitter release and novel methodology for identifying neurotransmitter release blockers |
| 5767162, | Mar 02 1990 | State of Oregon, Acting by and Through the Oregon State Board of Higher | Tri-and tetra-substituted guanidines and their use as excitatory amino acid antagonists |
| 5798390, | Mar 02 1990 | State of Oregon, Acting by and Through the Oregon State Board of Higher | Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists |
| 5837737, | Feb 08 1991 | Wyeth | Hydrazinedicarboximidamide compounds and pharmaceutical composition comprising same |
| 5847006, | Feb 08 1991 | Wyeth | Therapeutic guanidines |
| 5850840, | Dec 26 1995 | ALTEON, INC | Methods for measurement and treatment predicated on the presence of advanced glycosylation endproducts in tobacco and its combustion byproducts |
| 5852009, | Mar 19 1984 | ROCKEFELLER UNIVERSITY, THE | Compositions, including pharmaceutical compositions, for inhibiting the advanced glycosylation of proteins, and therapeutic methods based thereon |
| 5877217, | Dec 23 1996 | ALTEON INC | N-acylaminoalkyl-hydrazinecarboximidamides |
| 5955507, | Jun 02 1995 | Wyeth | Therapeutic substituted guanidines |
| 6013675, | Nov 23 1993 | Wyeth | Therapeutic substituted guanidines |
| 6025355, | May 19 1997 | Wyeth | Pharmaceutically active compounds and methods of use |
| 6071969, | Feb 08 1991 | Wyeth | Substituted aminoguanidines and methods of use thereof |
| 6072075, | May 22 1997 | Regents of the University of California, The | Guanidinylation reagents |
| 6110968, | Dec 26 1995 | ALTEON, INC | Methods for treatment predicated on the presence of advanced glycosylation endproducts in tobacco and its combustion byproducts |
| 6114323, | Mar 19 1984 | The Rockefeller University | Methods for inhibiting the advanced glycosylation of proteins |
| 6143791, | Feb 03 1994 | Wyeth | Therapeutic guanidines |
| 6147063, | May 27 1993 | CeNeS Limited | Therapeutic substituted guanidines |
| 6153604, | May 27 1993 | CeNeS Limited | Therapeutic substituted guanidines |
| 6156741, | May 27 1993 | CeNeS Limited | Therapeutic substituted guanidines |
| 6174924, | Feb 03 1994 | Wyeth | Therapeutic guanidines |
| 6242198, | Jul 25 1996 | Wyeth | Methods of treatment of eye trauma and disorders |
| 6251948, | Mar 02 1990 | State of Oregon, Acting by and Through the Oregon State Board of Higher | Tri-and tetra-substituted guanidines and their use as excitatory amino acid antagonists |
| 6288123, | Feb 03 1994 | Wyeth | Therapeutic guanidines |
| 6358696, | Jul 25 1996 | Wyeth | Methods of treatment of eye trauma and disorders |
| 6358993, | Feb 15 1996 | Wyeth | Pharmaceutically active nitrogen ring compounds and methods of use thereof |
| 6380358, | May 22 1997 | The Regents of the University of California | Guanidinylation reagents |
| 6673557, | Jul 25 1996 | Wyeth | Methods of treatment of eye trauma and disorders |
| 6756389, | Aug 09 1996 | Wyeth | Pharmaceutically active compounds and methods of use |
| 6787569, | Feb 03 1994 | Wyeth | Therapeutic guanidines |
| 7351743, | Feb 03 1994 | Wyeth | Therapeutic guanidines |
| 7423059, | Aug 09 1996 | Wyeth | Pharmaceutically active compounds and methods of use |
| 8642771, | Dec 24 2009 | Saudi Aramco Technologies Company | Methods for the synthesis of polycyclic guanidine compounds |
| 9738647, | Dec 24 2009 | Saudi Aramco Technologies Company | Methods for the synthesis of polycyclic guanidine compounds |
| Patent | Priority | Assignee | Title |
| 3274230, | |||
| 3308094, | |||
| FR2019933, | |||
| GB1208252, | |||
| GB1233420, |
| Executed on | Assignor | Assignee | Conveyance | Frame | Reel | Doc |
| Jun 12 1982 | BARTON, DEREK H R | CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE 15 QUAI ANATOLE FRANCE 75007 PARIS -FRANCE | ASSIGNMENT OF ASSIGNORS INTEREST | 004027 | /0344 | |
| Jun 12 1982 | ELLIOTT, JOHN D | CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE 15 QUAI ANATOLE FRANCE 75007 PARIS -FRANCE | ASSIGNMENT OF ASSIGNORS INTEREST | 004027 | /0344 | |
| Jun 12 1982 | GERO, STEPHAN D | CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE 15 QUAI ANATOLE FRANCE 75007 PARIS -FRANCE | ASSIGNMENT OF ASSIGNORS INTEREST | 004027 | /0344 | |
| Jul 14 1982 | Centre National de la Recherche Scientifique (CNRS) | (assignment on the face of the patent) | / |
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